Giardia lamblia infection in both endemic and epidemic in the United State. It is a major cause of waterborne enteric disease throughout the world and is particulary prevalent in children. The clinical course of giardiasis is quite variable. Symptoms range from absent to severe diarrhea and malabsorption and fairlure to thrive in children. Infections may rapidly clear spontaneously or persist for years. It is likely that nonimmune, as well as immune, defenses in fluence the course and severity of the disease. Three major hypotheses will be tested in the proposed project: (1) Nonimmune secretory defenses exist in the human duodenum which inhibit or kill G. lamblia and may, therefore, protect the host; (2) Parasites may be protected from these by other intestinal secretory factors; and (3) Secretory antibodies to G. lamblia inhibit attachment of trophozoites, rather than killing them. Preliminary results support these hypotheses. Lactoferrin (Lf), an iron-binding protein secreted into duodenal fluid, bound to G. lamblia trophozoites in vivo and killed them. The parasites were also killed by pancreatic lipase, but not by trypsin. Factors which protected the parasites from killing by lipase were albumin and bile salts. Lf and a lipase are also concentrated in human milk. The preliminary studies revealed that G. lamblia was also killed by normal human milk (90% killing in 17 minutes by 3% milk). The objectives of this project are: (1) to positively identify nonimmune secretory factors present in the human duodenum and milk which inhibit G. lamblia in vitro; (2) to examine the effects of these factors on parasite attachment and survival; (3) to elucidate the mechanisms of nonimmune killing on the cellular and biochemical levels; (4) to identify and isolate secretory antibodies to G. lamblia and to examine their effects on trophozoite attachment and survival in vitro; and (5) to identify other secretory factors which promote parasite survival of the nonimmune and immune defenses. Information gained from these studies may provide a better basis for understanding the influence of immune and nonimmune host secretory factors upon the clinical course of human giardiasis.